Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

// Veronica De Simone 1 , Giulia Ronchetti 1 , Eleonora Franzè 1 , Alfredo Colantoni 1 , Angela Ortenzi 1 , Massimo C. Fantini 1 , Angelamaria Rizzo 1 , Giuseppe S. Sica 2 , Pierpaolo Sileri 2 , Piero Rossi 2 , Thomas T. MacDonald 3 , Francesco Pallone 1 , Giovanni Monteleone 1 and Carmine Stolfi 1 1 Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy 2 Department of Surgery, University of Rome “Tor Vergata”, Rome, Italy 3 Centre for Immunology and Infectious Disease, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK Correspondence to: Carmine Stolfi, email: // Keywords : Apc min/+ mice, STAT3, COX-2/PGE2, VEGF Received : September 22, 2014 Accepted : February 17, 2015 Published : March 12, 2015 Abstract Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc min/+ mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc min/+ mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.